Polymers

ABSTRACT

Described herein are polymers and associated methods to occlude structures and malformations of the vasculature with polymers with delayed controlled rates of expansion. Methods of forming such devices are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/179,212, filed Jun. 10, 2016, which claims the benefit of U.S.provisional patent application No. 62/174,425, filed Jun. 11, 2015, theentire disclosure of each of which are incorporated herein by reference.

FIELD

The present invention relates generally to expansile polymers andmedical treatment methods using the polymers.

SUMMARY

Described herein generally are expansile polymers such as hydrogels. Thepolymers can be formed as filaments. Methods of forming these polymersare also described. Further, medical treatment methods using thepolymers are described. In some embodiments, when formed as a filament,the filaments described herein possess enough structural strength to notrequire support members. In other embodiments, the hydrogel filamentsrequire support members. The filaments can also be opacified in order tovisualize the filaments using medically relevant imaging techniques.

In one embodiment described herein are expansile devices forimplantation in an animal, such as a mammal, such as a human. Theexpansile devices can comprise an expansile polymer including a reactionproduct of a polymerization solution including a macromer, a monomer, afirst crosslinker, and a second crosslinker. In some embodiments, thesecond crosslinker is cleavable. In some embodiments, the secondcleavable crosslinker imparts a secondary expansion to the expansilepolymer.

The expansile devices can include at least one visualization element,which can be metallic powders, gadolinium, superparamagnetic iron oxideparticles, barium sulfate, or a combination thereof. In one embodiment,the at least one visualization element is barium sulfate.

The monomer used in the herein described polymers can be pH sensitiveand provide a first expansion to the expansile polymer. In otherembodiments, the monomer may not be pH sensitive. In other embodiments,a monomer may not be used. In some embodiments, a macromer may be pHsensitive and/or provide expansion characteristics to the polymer. Insome embodiments, the macromers and the monomers may have expansioncharacteristics.

In some embodiments, the first crosslinker can beN,N′-methylenebisacrylamide.

The second cleavable crosslinker can be an acrylate based crosslinkersuch as a methacrylate based crosslinker. In some embodiments, thesecond cleavable crosslinker can be an acrylic anhydride basedcrosslinker. The acrylic anhydride can be a methacrylate based anhydridecrosslinker and can have a structure

wherein n is 0, 1, 2, 3, 4, or 5. Further, the acrylic anhydride basedcrosslinker can be synthesized by reaction of a di-acid with methacrylicanhydride.

Methods of forming expansile polymers are also described. Methods cancomprise polymerizing a polymer from a polymerization solutioncomprising a macromer, a monomer, a first crosslinker, and a secondcleavable crosslinker. The methods can further include a step oftreating said polymer in a non-physiological pH for a predeterminedamount of time thereby creating an environmentally responsive hydrogel.

In some embodiments, the non-physiological pH that the polymers aretreated in can be basic. In other embodiments, the non-physiological pHcan be acidic.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts Scheme 2 showing a cleavable second type of crosslinkerincluded in the hydrogel structure or matrix.

DETAILED DESCRIPTION

Described herein generally are expansile polymers such as hydrogels. Thepolymers can be formed into virtually any shape or form. In oneembodiment, the polymers can be formed as filaments or other elongatedstructures. The polymers can have tuned rates of expansion and canincorporate a secondary expansion mechanism by including a crosslinkerthat can cleave upon a particular physiological event and allowexpansion to what the polymer would normally expand to without thecleavable crosslinker. In other words, cleavable crosslinks can preventfull expansion or retard expansion until a cleavable event occurs andthe polymer can fully expand.

Methods of forming the polymers are also described herein, includingmethods of making the polymers environmentally responsive and expandableat a predetermined rate for a predetermined amount of time. Thisexpansion rate can be tailored using at least the secondary expansionmechanism by incorporation of a second cleavable crosslinker. Polymerexpansion can be further tailored by including different types ofcleavable crosslinkers such as a third, fourth, fifth or subsequentcleavable crosslinkers. In other embodiments, expansion can be tailoredby using a different density or concentration of cleavable crosslinkers.

The expansile polymers and associated methods are for occludingstructures and malformations resulting from one or more cerebral and/orperipheral vascular diseases. The polymers can have delayed and/orcontrolled rates of expansion. These controlled rates of expansion givesurgeons a sufficient amount of time to deliver the polymer through amicrocatheter or catheter filled with blood or saline at physiologicalpH without the need to rush as a result of immediate expansion. For usewith a catheter, a polymer filament may be desired. Further, thepolymers can include one or more visualization agents, for example,radiopaque elements or fillers to allow visualization duringimplantation.

Generally, the polymers, e.g., hydrogel filaments, can be deployedwithin the vasculature using standard practices andmicrocatheters/catheters to occlude blood flow.

As used herein, the term “environmentally responsive” refers to amaterial (e.g., a hydrogel or polymer described herein) that issensitive to changes in environment including but not limited to pH,temperature, and pressure. Many of the expansile materials describedherein are environmentally responsive at physiological conditions.

As used herein, the term “non-resorbable” refers to a material (e.g., ahydrogel) that cannot be readily and/or substantially degraded and/orabsorbed by bodily tissues.

As used herein, the term “unexpanded” refers to the state at which ahydrogel is substantially not hydrated and, therefore, not expanded. Insome embodiments described herein, a hydrogel filament is generallyunexpanded prior to implantation into a patient.

As used herein, the term “ethylenically unsaturated” refers to achemical entity (e.g., a macromer, monomer or polymer) containing atleast one carbon-carbon double bond.

In some embodiments, when formed as a filament or other elongatedstructure, the filaments described herein may not have support members,such as no metal or metallic support members, to aid in supporting thefilaments before, during and after implantation. When formed as afilament or other elongated structure, the filaments can possess enoughstructural column strength to not require support members.

The polymers described when provided as filaments or other elongatedstructures can have round, square, rectangular, triangular, pentagonal,hexagonal, heptagonal, octagonal, ellipsoidal, rhomboidal, torx, orstar-shaped cross-sectional shapes. A filament can be described ashaving a three dimensional shape such as, but not limited to a thread,string, hair, cylinder, fiber, or the like. The filament can beelongated meaning that its length exceeds its width or diameter by atleast 5, 10, 15, 20, 50, 100, 500, 1,000 or more times.

The filaments can be delivered through a catheter or microcatheter usinga liquid flush (e.g. saline). The filaments have sufficient columnstrength to alleviate the need for a metal support member, yet soft andflexible enough to navigate through vasculature. However, in someembodiments, the filaments described herein do not have sufficientcolumn strength to be advanced out of a catheter device by pushing witha metal wire. Here, as described above, a liquid flush, in some cases apressurized liquid flush, can be used to advance the filaments throughand out of a catheter or microcatheter.

The polymers described herein can be formed from polymerizationsolutions or prepolymer solutions comprising such components as one ormore solvent(s), one or more macromer(s), one or more monomer(s), one ormore cross-linker(s), one or more visualization agent(s), and one ormore initiator(s). Some components are optional. In one embodiment, thehydrogel filaments can include a polymer which can be a reaction productof (i) one or more macromers, (ii) one or more monomers, and/or (iii)two or more different crosslinkers, wherein one of the crosslinkers is acleavable crosslinker. The polymers can also optionally include one ormore pharmaceutical agents. The polymers can also include one or morevisualization agents.

A particular combination of monomers/macromers/crosslinkers can providediffering polymeric physical properties. Different polymeric physicalproperties can include, but are not limited to tensile strength,elasticity, and/or delivery through a microcatheter or catheter.

The solvent's function in the polymerization solution is completedissolution of all macromers, monomers, cross-linkers, initiators,and/or soluble visualization agents needed to form a particularfilament. In other embodiments, the solvent can dissolve substantiallyall of the macromers, monomers, cross-linkers, initiators, and/orsoluble visualization agents needed to form a particular filament. Insome embodiments, the visualization agent or agents do not dissolve inthe solvent.

If a liquid monomer (e.g. 2-hydroxyethyl methacrylate) is used, asolvent may not be necessary. The solvent, if necessary, is selectedbased on the solubility of the components of the polymerizationsolution. Solvents can include isopropanol, ethanol, water,dichloromethane, and acetone. However, any number of solvents can beutilized and a skilled artisan can match a solvent to a particularpolymer system.

Solvent concentrations can range from about 20% w/w to about 80% w/w ofthe polymerization solution. In other embodiments, the solvent rangesfrom about 40% w/w to about 60% w/w or about 30% w/w to about 50% w/w.In one embodiment, the solvent makes up about 40% w/w of thepolymerization solution.

Macromers described herein can include large molecular weight compoundssuch as polymers having one or more reactive groups. In someembodiments, macromers with solubility in solvents and functional groupsamenable to modifications may be used. Polyethers, due to theirsolubility in a variety of solvents, their availability in a variety offorms, and their available hydroxyl groups, may be used as macromers.Other macromers can include, but are not limited to, poly(ethyleneglycol), poly(propylene glycol), and poly(tetramethylene oxide).

In other embodiments, a low molecular weight macromer can be used and/orin other embodiments, a branched macromer may be used. A low molecularweight, branched macromer can include at least three reactive moietiesper molecule so that a high crosslink density of the finalized polymercan be achieved. Example low molecular weight, branched macromers caninclude ethoxylated pentaerythritol having four end groups per molecule,and ethoxylated trimethylolpropane having three end groups per molecule.

In still other embodiments, non-polyether polymers with functionalgroups available for modification, such as poly(vinyl alcohol), can alsobe used as macromers.

Macromers can be present at a concentration of about 10% w/w, about 15%w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about40% w/w, about 45% w/w, about 50% w/w, at least about 10% w/w, betweenabout 10% w/w and about 40% w/w, between about 15% w/w and about 25%w/w, between about 15% w/w and about 50% w/w, or between about 15% w/wand about 30% w/w, of the polymerization solution. In one embodiment,the macromer concentration is about 15% w/w of the polymerizationsolution.

The molecular weight of the macromer can alter the mechanical propertiesof the resulting polymer or hydrogel filament. In some embodiments, thealteration of the mechanical properties can be substantial. Smallermolecular weights result in polymers with sufficient column strength tobe pushed through microcatheters and catheters when formed as a filamentor other elongated structures. Larger molecular weights can result inpolymer filaments that can be pushed through microcatheters andcatheters with more difficulty. As such, the macromers described hereincan have a molecular weight of about 50 g/mole, about 100 g/mole, about200 g/mole, about 300 g/mole, about 400 g/mole, about 500 g/mole, about1,000 g/mole, about 1,500 g/mole, about 2,000 g/mole, about 2,500g/mole, about 3,000 g/mole, about 3,500 g/mole, about 4,000 g/mole,about 4,500 g/mole, about 5,000 g/mole, at least about 50 g/mole, atleast about 100 g/mole, between about 50 g/mole and about 5,000 g/mole,between about 100 g/mole and about 5,000 g/mole, between about 1,000g/mole and about 5,000 g/mole, between about 100 g/mole and about 1,000g/mole, or between about 500 g/mole and about 1,000 g/mole. In oneembodiment, the molecular weight is between about 500 g/mole to about1,500 g/mole.

The polymerization solutions can include at least one macromer. Themacromer can be of low molecular weight, shapeable, multifunctional(e.g. difunctional), ethylenically unsaturated or a combination thereof.At least one of the macromer's roles is to impart the desired mechanicalproperties and/or structural framework to the herein described polymers.In general, any polymer can function as a macromer. However, polymerswith solubility in solvents and functional groups amenable tomodifications can also be used. Polyethers, due to their solubility in avariety of solvents, their availability in a variety of forms, and theiravailable hydroxyl groups, can be used. Poly(ethylene glycol),poly(propylene glycol), ethoxylated trimethylol propane, andpoly(tetramethylene oxide) can all be suitable for use herein. Inanother embodiment, a macromer can be poly(ethylene glycol).Poly(ethylene glycol) is preferred because of its solubility in aqueoussolutions. Likewise, cross-linked networks of poly(ethylene glycol)swell in aqueous solutions. Non-polyether polymers with functionalgroups available for modification, such as poly(vinyl alcohol), can alsobe utilized as macromers. Macromer concentrations can range from about5% w/w to about 50% w/w, about 10% w/w to about 40% w/w, about 15% w/wto about 30% w/w, or about 16% w/w to about 29% w/w of thepolymerization solution. In one embodiment, the macromer concentrationis about 19% w/w, about 25% w/w or about 29% w/w of the polymerizationsolution.

In some embodiments, the macromer is shapeable. Shapeability describesthe macromer's relative rigidity and its ability to hold a particularshape. For example, a shapeable macromer according to the presentdescription can be formed using a device such as a mandrel and can holdthe resulting shape for implantation.

The molecular weight of the macromer can dramatically change theresulting polymer's mechanical properties. Smaller molecular weightsresult in polymers when formed as filaments that have sufficient columnstrength to be pushed through microcatheters and catheters. Largermolecular weights result in polymers that when formed as filaments, canrequire more effort to be pushed through microcatheters and catheters.

The macromers described herein have a molecular weight ranging fromabout 100 g/mole to about 100,000 g/mole or about 500 g/mole to about50,000 g/mole. In one embodiment, molecular weight ranges from about5,000 g/mole to about 15,000 g/mole. In another embodiment, themolecular weight is about 10,000 g/mole. One embodiment includespoly(ethylene glycol) diacrylamide with a molecular weight of about10,000 g/mole.

Any functional groups associated with the macromers described can bederivatized. The functional groups of the macromers can be derivatizedto impart ethylenically unsaturated moieties allowing free radicalpolymerization of the hydrogel. Functionalities for free radicalpolymerization can include acrylates, methacrylates, acrylamides, vinylgroups, and derivatives thereof. Alternatively, other reactivechemistries can be employed to polymerize the hydrogel, for example,nucleophile/N-hydroxysuccinimde esters, nucleophile/halide, vinylsulfone or maleimide. In one embodiment, a functional group of themacromer is an acrylate.

Biostability (or non restorability) or biodegradation can be imparted topolymers described by altering the synthetic route to derivatizemacromer functional groups. If biostability is desired, linkagestability in the physiological environment can be utilized. In oneembodiment, a biostable linkage is an amide. The macromer hydroxylgroup(s) is converted to an amino group followed by reaction withacryloyl chloride to form an acrylamide group. If biodegradation isdesired, linkages susceptible to breakage in a physiological environmentcan be utilized. In some embodiments, biodegradable linkages can includeesters, polyesters, and amino acid sequences degradable by enzymes.

Monomers used to form the herein described polymers can have lowmolecular weights and/or can contain a single polymerizable group. Ifpresent, the monomer(s) can aid in polymerization and impart specificmechanical properties to the resulting polymer. The monomers can be anymolecule with a single functionality and conducive to a desiredmechanical property.

Specific monomers can include, but are not limited to, t-butylacrylamide, 2-hydroxyethyl methacrylate, hydroxyl propyl acrylate,hydroxyl butylacrylate, and derivatives thereof. The hydrophobicity andbulky structure of these specific monomers can impart column strength tothe resulting polymer.

In some embodiments, a visualization agent can be a monomer andincorporated into the polymeric structure.

Monomers, if present, can be present at a concentration of about 5% w/w,about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30%w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, atleast about 5% w/w, between about 5% w/w and about 40% w/w, betweenabout 10% w/w and about 50% w/w, between about 5% w/w and about 30% w/w,or between about 5% w/w and about 20% w/w, of the prepolymer solution.

Monomers sensitive to pH can be utilized in the polymers describedherein thereby imparting environmental sensitivity to them. The mainfunction of the pH sensitive monomer is to permit control over thepolymer's rate of expansion. Such monomers must include functionalityallowing incorporation into the resulting polymer during polymerizationand ionizable moieties, for example, carboxylic acids or amines.Concentrations of pH sensitive monomers in the polymerization solutioncan range from about 1% to about 12.5%. In some embodiments, pHsensitive monomers can be acrylic acid, methacrylic acid, aminomethacrylate, amino methacrylamide, and derivatives and salts thereof.In some embodiments, pH sensitive monomers are not utilized.

Generally, the controlled rate of expansion of the polymers is impartedthrough the incorporation of ethylenically unsaturated monomers withionizable functional groups, (e.g. acidic or basic groups). For example,if acrylic acid is incorporated into the cross-linked polymeric network,it can be introduced through a microcatheter filled with blood or salineat physiological pH. The polymer cannot and may not expand until thecarboxylic acid groups deprotonate. Conversely, if a basic, aminecontaining monomer is incorporated into the cross-linked network, thepolymer can be introduced through a microcatheter filled with blood orsaline at physiological pH. The polymer cannot and will not fully expanduntil the amine groups are protonated.

In one embodiment, pH-sensitive monomers are incorporated into thepolymers to control the rate of expansion to permit delivery throughmicrocatheters and catheters filled with physiological fluids. In oneembodiment, ethylenically unsaturated carboxylic acids are incorporatedinto the polymers. In another embodiment, salts of ethylenicallyunsaturated carboxylic acids are incorporated into the polymers andsubsequently the polymers are incubated in a low pH solution toprotonate all the salts of the carboxylic acids. Expansion occurs in aphysiological environment as the carboxylic acids deprotonate. Inanother embodiment, salts of ethylenically unsaturated amines areincorporated into the polymers and subsequently the polymers areincubated in a high pH solution to deprotonate the salts of the amines.Expansion occurs in a physiological environment as the amines protonate.In yet another environment, pH sensitive monomers are not incorporatedinto the polymers.

Non-pH sensitive monomers can also be used to aid in polymerization ofthe polymers and impart specific mechanical properties to the polymers.The non-pH sensitive monomers can be any molecule with a singlefunctionality to incorporate into the polymers and/or a structureconducive to the desired mechanical property. The non-pH sensitivemonomers can be, for example, hydrophobic thereby imparting columnstrength to the polymers. Also or in addition, the non-pH sensitivepolymers can have a bulky structure further imparting column strength.Internal hydrogen bonding within the non-pH sensitive monomer impartsincreasing tensile strength. In some embodiments, non-pH sensitivemonomers can be t-butyl acrylamide, 2-hydroxyethyl methacrylate, andderivatives thereof. Concentrations of non-pH sensitive monomers canrange from about 0% to about 20% w/w, about 15% w/w, about 12% w/w orabout 11% w/w of the polymerization solution.

In one embodiment, depending on the monomers chosen for a particularpolymer, significant fluid uptake by the polymer can occur and a largeincrease in the volume of the polymer can occur in a physiologicalenvironment. In another embodiment, monomers chosen allow only a smallamount of fluid uptake by the polymer and only a small increase in thevolume of the polymer occurs in a physiological environment. In yetanother environment, monomers chosen prevent fluid uptake by the polymerand the volume of the polymer remains unchanged in a physiologicalenvironment.

Crosslinkers can also be utilized to impart cross-linking of theresulting polymer. A crosslinker can be any molecule with at least twofunctionalities to incorporate into the resulting polymer. Thecrosslinker can also be a structure conducive to the desired mechanicalproperty imparted on the finalized polymer.

Crosslinkers can include an ester, a carbonate, a thioester, ananhydride, or a combination thereof. In other embodiments, multiples ofeach of an ester, a carbonate, anhydrides, and/or a thioester can beincluded. In one embodiment, a crosslinker can be an anhydride.

Other crosslinkers can include N,N-methylenebisacrylamide and ethyleneglycol dimethacrylate.

Cross-linker(s), when used in the described polymers, impart desiredmechanical properties. The cross-linker can be any molecule with atleast two functionalities to incorporate into the polymers andpreferably a structure conducive to the desired mechanical property. Inone embodiment, a cross-linker is N,N-methylenebisacrylamide.Concentrations of the cross-linker can be less than about 1% w/w, lessthan about 0.8% w/w, less than about 0.5% w/w, or less than about 0.1%w/w of the polymerization solution. In one embodiment, the concentrationof cross-linker is about 1% w/w.

A second type of crosslinker can also be included in the final polymer.The second type of crosslinker can impart a secondary mechanism ofexpansion to the hydrogel filaments. This secondary mechanism can be onethat increases the swelling size of the hydrogel, but does not impactthe initial rate of swelling. In some embodiments, the second type ofcrosslinker can retard full expansion of the polymer until thecrosslinker is cleaved.

Possibilities for a second type of crosslinker can include crosslinkersthat can be cleaved or degraded. For example, cleavable linkages includeesters, polyesters, and amino acid sequences degradable by enzymes. Inother embodiments, the second type of crosslinker can includehydrolyzable moieties such as anhydrides. Anhydrides will begin tocleave as the hydrogel hydrates. However, in some embodiments, thecleavage rate may be slower than that of the initial expansion of thehydrogel resulting from hydration.

Cleavable crosslinkers can include acrylate based crosslinkers such asacrylic anhydride based crosslinkers. These crosslinkers can besynthesized by reaction of a di-acid with methacrylic anhydride. Anexample synthetic scheme (Scheme 1) is

wherein n is 0, 1, 2, 3, 4, or 5.

In some embodiments, the di-acid crosslinker can include ethylene,ethylene glycol, or propylene glycol repeating units to modulate thewater solubility and the rate of degradation.

In some embodiments, when an anhydride based crosslinker is used, aresulting polymer can be sensitive to water. Thus, in some embodiments,gelation and purification of the resulting polymer can be performed inthe absence of water.

In one embodiment, a first type of crosslinker and a second type ofcrosslinker can be used in the herein described hydrogels and polymers.In one embodiment, the second crosslinker can be a cleavablecrosslinker. For example, as illustrated FIG. 1 in Scheme 2, a cleavablesecond type of crosslinker is included in the hydrogel structure ormatrix.

The second type of crosslinker can incorporate secondary covalentcleavable crosslinks, in addition to a first type of permanentcrosslinks, into the backbone. As these secondary covalent cleavablecrosslinks are broken the polymer or hydrogel can expand to a largerdiameter than the hydrogel would expand without the secondarycrosslinkers present. In other words, hydrogels incorporating a secondcleavable crosslinker in addition to a first permanent crosslinker canhave a first expanded diameter when the hydrogel is swollen and asecond, larger diameter when the cleavable crosslinks are broken orcleaved.

In effect, the hydrogel can initially expand to the extents limited bythe initial crosslink density imparted by the cleavable crosslinks(e.g., the first diameter), and then subsequent hydrolysis of thecleavable crosslinks can allow the hydrogel to expand to a greater size(e.g., the second diameter).

In further embodiments, a third, fourth, fifth or more differentcleavable crosslinkers can be included in a polymer or hydrogeldescribed. Each cleavable crosslinker can have a different length anddifferent degradation time to allow multiple steps of expansion before afinal expansion size is achieved.

In some embodiments, the concentration of the second, cleavable type ofcrosslinker can be about 5% w/w, about 4% w/w, about 3% w/w, about 2%w/w, about 1% w/w, about 0.5% w/w between about 5% w/w and about 1% w/w,between about 2% w/w and about 0.5% w/w, or between about 5% w/w andabout 0.5% w/w of the polymerization solution.

The concentration of all the crosslinkers in a polymerization solutioncan be less than about 10% w/w, less than about 5% w/w, less than about4% w/w, less than about 3% w/w, less than about 2% w/w, less than about1% w/w, or less than about 0.5% w/w of the polymerization solution.

In one embodiment, polymerization of the herein described polymers canbe initiated using an initiator. An initiator can beazobisisobutyronitrile (AIBN) or a water soluble AIBN derivative. Otherinitiators useful according to the present description includeN,N,N′,N′-tetramethylethylenediamine, ammonium persulfate, benzoylperoxides, 2,2′-azobis(2-methylpropionamidine)dihydrochloride, andcombinations thereof, including azobisisobutyronitriles. Thepolymerization solution can be polymerized by reduction-oxidation,radiation, heat, or any other method known in the art. Radiationcross-linking of the polymerization solution can be achieved withultraviolet light or visible light with suitable initiators or ionizingradiation (for example, electron beam or gamma ray) without initiators.Cross-linking can be achieved by application of heat, either byconventionally heating the solution using a heat source such as aheating well, or by application of infrared light to the polymerizationsolution.

When used in the polymerization solutions described herein, an initiatorstarts the polymerization of the polymerization solution components. Anexemplary initiator includes2,2′-azobis(2-methylpropionamidine)dihydrochloride. Concentrations ofthe initiator can be less than about 1% w/w or less than about 0.5% w/wof the polymerization solution.

Visualization agents can also be added to the polymers described hereinsince metallic support members may not be used in conjunction with thepresently described polymers. Generally, in the art, metallic supportmembers aid in the visualization of embolic devices. Here, this may notbe the case. The visualization agents impart visibility of the resultingpolymers when imaged using a medically relevant imaging technique suchas fluoroscopy, computed tomography, or magnetic resonance techniques.

Visualization of the polymers under fluoroscopy can be imparted by theincorporation of solid particles of radiopaque materials such as barium,bismuth, tantalum, platinum, gold, and other heavy nuclei species intothe polymers or by the incorporation of iodine molecules polymerizedinto the polymer structure. In one embodiment, a visualization agent forfluoroscopy can be barium sulfate. Visualization of the polymers undercomputed tomography imaging can be imparted by incorporation of solidparticles of barium or bismuth. Metals visible under fluoroscopygenerally result in beam hardening artifacts that preclude theusefulness of computed tomography imaging for medical purposes. In oneembodiment, a visualization agent for fluoroscopy can be barium sulfate.Concentrations of barium sulfate rendering the hydrogel filamentsvisible using fluoroscopic and computed tomography imaging can rangefrom about 30% w/w to about 60% w/w, about 35% w/w to about 50% w/w, orabout 39% w/w to about 47% w/w of the polymerization solution.

Visualization of the polymers under magnetic resonance imaging can beimparted by the incorporation of solid particles of superparamagneticiron oxide or gadolinium molecules polymerized into the polymerstructure. In one embodiment, a visualization agent for magneticresonance is superparamagnetic iron oxide with a particle size of 10microns. Concentrations of superparamagnetic iron oxide particles torender the polymers visible using magnetic resonance imaging can rangefrom about 0.01% w/w to about 1% w/w, about 0.05% w/w to about 0.5% w/w,or about 0.1% w/w to about 0.6% w/w of the polymerization solution.

In one embodiment, a polymer can be formed from a reaction product of adifunctional, low molecular weight, ethylenically unsaturated, shapeablemacromer, an ethylenically unsaturated monomer, a visualization element,a cross-linker, a second cleavable crosslinker that retards expansion ofthe polymer, and an initiator.

In another embodiment, a polymer can include a difunctional, lowmolecular weight, ethylenically unsaturated, shapeable macromer, anethylenically unsaturated monomer, a visualization element, across-linker, and a second cleavable crosslinker that retards expansionof the polymer.

The polymers can have many characteristic properties one of which isbending resistance. The polymers when formed as filaments or otherelongated structures can generally have a dry bending resistance ofabout 20 mg to about 200 mg, about 20 mg to about 32 mg or about 100 mgto about 200 mg. In the wet state, the bending resistance lowersdrastically to about 2 mg to about 50 mg, about 2 mg to about 5 mg, orabout 25 mg to about 50 mg.

Another characteristic is average ultimate tensile strength of thepolymers when formed as filaments or other elongated structures. Thefilaments described herein have an average ultimate tensile strength ofabout 0.18 lbf to about 0.65 lbf, about 0.18 lbf to about 0.25 lbf, orabout 0.52 lbf to about 0.65 lbf.

Methods of preparing the polymers is also described. The polymerizationsolution is prepared by dissolving the macromer, pH sensitive monomers,non-pH sensitive monomers, cross-linker, cleavable crosslinker,initiator, and soluble visualization agents in the solvent. Afterdissolution of these components, an insoluble visualization agent can besuspended in the polymerization solution. Mixing of the polymerizationsolution containing an insoluble visualization agent with a homogenizeraids in suspension of the insoluble visualization agent. Thepolymerization solution can then be polymerized to provide a polymer.The polymer can be dried.

In some embodiments, to form a filament, before polymerization, thepolymerization solution can be injected into tubing with an innerdiameter ranging from about 0.001 inches to about 0.075 inches andincubated for several hours in boiling water, for example, at 100° C.,and subsequently overnight at 80° C. to complete the polymerization. Theimmersion in boiling water allows for rapid heat transfer from the waterto the polymerization solution contained in the tubing. The selection ofthe tubing imparts microcatheter or catheter compatibility. For deliverythrough microcatheters, tubing diameters can range from about 0.006inches to about 0.025 inches. For delivery through 4 and 5 Fr catheters,tubing can have diameters from about 0.026 inches to about 0.045 inches.In one embodiment, the tubing is made from HYTREL® (DuPont, Wilmington,Del.). The HYTREL® tubing can be dissolved in solvents, facilitatingremoval of the formed polymer from the tubing.

If a filament as described herein is wrapped around a mandrel prior topolymerization of the polymerization solution, the resulting polymerwill maintain the shape of the filament around the mandrel or at leastretain a memory of the shape. Using this technique, helical, tornado,and complex shapes can be imparted to the hydrogel filament. When thetubing is wrapped around a mandrel, trapezoidal and/or oval tubing canbe used. After wrapping around the mandrel, the oval shape of the tubingis rounded and the resulting filament has a round shape.

If HYTREL® tubing is utilized, the filament can be recovered byincubating the tubing in a solution of 25% w/w phenol in chloroformfollowed by washing in chloroform and ethanol. After the filament hasbeen washed, it is dried, and a dried hydrogel filament is produced. Thelength of a dried filament can range from about 0.01 cm to about 1,000cm, about 0.1 cm to about 500 cm, about 0.25 cm to about 250 cm, orabout 0.5 cm to about 100 cm. The diameter of a filament can range fromabout 0.01 inches to about 0.1 inches, about 0.001 inches to about 0.01inches, or about 0.006 inches to about 0.075 inches. In one embodimentthe filament has a diameter less than about 0.05 inches, 0.04 inches, or0.031 inches.

In some embodiments, the polymer described herein can expand initially,before second crosslinker cleavage to about 5%, about 10%, about 20%,about 30%, about 40%, about 50%, at most about 50%, at most about 40%,or between about 10% and about 50% of the polymers full expansiondiameter. Then, after cleavage of the second crosslinker, the polymerdescribed herein can expand to about 50%, about 60%, about 70%, about80%, about 90%, 100%, at least about 50%, at least about 60%, or betweenabout 50% and 100% of the polymers full expansion diameter.

In some embodiments, the polymers described can be incubated in a low pHor high pH solution to protonate or depronate the pH sensitive monomerincorporated into the polymer as necessary rendering it environmentallyresponsive. The environmentally responsive polymer can expand to aparticular dimension after being subjected to a particular pHenvironment. However, the cleavable crosslinker can prevent the polymerfrom expanding to its full expansion parameters until the cleavablecrosslinkers have been broken and the polymer is allowed to follyexpand.

In some embodiments, the second cleavable crosslinker can add about 60sec, about 1 min, about 5 min, about 10 min, about 15, min, about 20min, at least about 1 min, at least about 5 min, or at least about 15min of time before the polymer is fully expanded.

Example 1 Implantation of a Polymer Filament with a Secondary ExpansionMechanism

A patient is implanted with a polymer filament which is crosslinked witha non-degradable crosslinker and a cleavable crosslinker and a pHsensitive monomer. The polymer filament had been treated in an acidic pHsolution and dried to render the filament environmentally responsive.

The filament is delivered through a microcatheter to a vessel occlusion.The filament expands in response to the change in pH. After about 10min, the filament is 50% expanded. After about 15 min, the filament isabout 60% expanded. At about 20 min, the cleavable corsslinking bondsbegin to break and after 25 min, the filament is about 95% expanded.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

We claim:
 1. A method of forming an expansile polymer, comprising:polymerizing a polymer from a polymerization solution comprising amacromer, a monomer, a first crosslinker, and a second cleavablecrosslinker, wherein the expansile polymer has a full expansion sizethat includes a primary expansion and a secondary expansion, wherein thesecondary expansion is retarded by the second cleavable crosslinker. 2.The method of claim 1, wherein the expansile device includes no supportmembers.
 3. The method of claim 1 further including at least onevisualization element.
 4. The method of claim 3, wherein the at leastone visualization element is selected from metallic powders, gadolinium,superparamagnetic iron oxide particles, or a combination thereof.
 5. Themethod of claim 3, wherein the at least one visualization element isbarium sulfate.
 6. The method of claim 1, wherein the monomer is pHsensitive and provides a first expansion to the expansile polymer. 7.The method of claim 1, wherein the second cleavable crosslinker is anacrylate based crosslinker.
 8. The method of claim 7, wherein theacrylate based crosslinker is an acrylic anhydride based crosslinker. 9.The method of claim 8, wherein the acrylic anhydride based crosslinkerhas a structure

wherein n is 0, 1, 2, 3, 4, or
 5. 10. The method of claim 8, wherein theacrylic anhydride based crosslinker is synthesized by reaction of adi-acid with methacrylic anhydride.
 11. The method of claim 1, whereinthe macromer is poly(tetramethylene oxide).
 12. The method of claim 1,further comprising treating said polymer in a non-physiological pH for apredetermined amount of time thereby creating an environmentallyresponsive hydrogel.
 13. The method of claim 12, wherein thenon-physiological pH is acidic.
 14. The method of claim 12, wherein thenon-physiological pH is basic.
 15. The method of claim 12 furtherincluding at least one visualization element.
 16. The method of claim15, wherein the at least one visualization element is a metallic powder,gadolinium, superparamagnetic iron oxide particles, barium sulfate, or acombination thereof.
 17. The method of claim 12, wherein the secondcleavable crosslinker is an acrylic anhydride based crosslinker.
 18. Themethod of claim 17, wherein the acrylic anhydride based crosslinker hasa structure

wherein n is 0, 1, 2, 3, 4, or
 5. 19. The method of claim 17, whereinthe acrylic anhydride based crosslinker is synthesized by reaction of adi-acid with methacrylic anhydride.
 20. The method of claim 1, whereinthe first crosslinker is N,N′-methylenebisacrylamide.
 21. The method ofclaim 1, wherein the expansile polymer has a dry bending resistance towet bending resistance ratio of about 200:50 to about 20:2, a drybending resistance of about 20 mg to about 200 mg, and a wet bendingresistance of about 2 mg to about 50 mg.